The term “nervous system injury” refers to any injury of the nervous tissue and can be caused by fracture or penetration of the skull or vertebra (such as in the case of a vehicle accident, fall or gunshot wound resulting in damage to the brain or spinal cord ), a disease process (neurotoxins, infections, tumors, metabolic abnormalities, genetic abnormalities, degenerative nerve diseases, etc.), a closed head injury such as rapid acceleration or deceleration of the head (i.e. Shaken Baby Syndrome) causing injury to the brain, or an injury or disease affecting the peripheral nerves. Such injuries can have devastating lifelong effects on physical and mental functioning.
Traumatic Brain Injury (TBI)—There are many complications associated with brain injury. For example, ˜25% of patients with brain contusions or hematomas and ˜50% of patients with penetrating head injuries will develop immediate seizures that occur within the first 24 hours of the injury. These immediate seizures increase the risk of early seizures which are defined as seizures occurring within one week after injury. However, these seizures do not seem to be linked to the development of post-traumatic epilepsy (recurrent seizures occurring >1 week after initial trauma).
Another complication of brain injury is hydrocephalus or post-traumatic ventricular enlargement. This complication occurs when cerebrospinal fluid (CSF) accumulates in the brain resulting in dilation of the cerebral ventricles and an increase in intracranial pressure (ICP). This condition can develop during the acute stage of brain injury or may not appear until later. Treatment includes shunting and draining of CSF as well as treatment for the root cause of the condition.
Another complication is when CSF leaks occur following tearing of the meningeal layers that cover the brain. This often occurs following skull fracture. A tear between the dura and the arachnoid membranes can cause CSF to leak out of the subarachnoid space into the subdural space. CSF can also leak from the nose and the ear. In addition, tears that allow CSF to leak out of the brain cavity can also allow air and bacteria into the cavity, possibly causing infections such as meningitis. Infections within the intracranial cavity are a dangerous complication of brain injury. They may occur outside of the dura mater, below the dura, below the arachnoid membrane or within the brain itself (abscess). Most of these complications develop within a few weeks of the initial trauma and result from skull fractures or penetrating injuries. Standard treatment involves antibiotics and sometimes surgery to remove the infected tissue. Meningitis may be especially dangerous, with the potential to spread to the rest of the brain and nervous system.
Any damage to the head or brain generally will cause some degree of damage to the vascular system serving the brain. While the body can repair damage to small blood vessels, damage to larger vessels can result in serious complications. For example, damage to one of the major arteries leading to the brain can cause a stroke, either through bleeding from the artery (hemorrhagic stroke) or through the formation of a clot at the site of injury (thrombus or thrombosis), blocking blood flow to the brain (ischemic stroke). Other types of vascular injuries include vasospasm and the formation of aneurysms. The methods of the invention are also suitable for treating stroke and related complications.
Skull fractures, especially at the base of the skull, can cause cranial nerve injuries that result in compressive cranial neuropathies. All but 3 of the 12 cranial nerves project out from the brainstem to the head and face. The seventh cranial nerve, called the facial nerve, is the most commonly injured cranial nerve in brain injury and damage to it can result in paralysis of facial muscles.
Pain, especially headache, is commonly a significant complication for conscious patients following brain injury. Serious complications for patients who are unconscious, in a coma or in a vegetative state include bed or pressure sores, recurrent bladder infections, pneumonia and other life-threatening infections, and progressive multiple organ failure.
Other complications caused by brain injuries include becoming paraplegia or quadriplegia.
TBI is the signature injury of the Iraq conflict (Okie (2005) NEJM 352(20):2043-2047; Okie (2006) NEJM 355:2609-2615; Vasterling et al, (2006) JAMA 296:519-529; Taber et al, (2006) J Neuropsychiatry Clin Neurosci 18:141-145; Das et al, (2005) NEJM 353: 633-634). TBI and its association with post-traumatic stress disorder (PTS) are in the news every day with the latest information revealing that 30% of the injured military population returns home from Iraq with TBI.
Treatment options for brain injury patients can involve surgery, draining of fluids and rehabilitation. Approximately half of severely head-injured patients will need surgery to remove or repair hematomas or contusions. When an injury occurs inside the skull-encased brain, there is no place for swollen tissues to expand and no adjoining tissues to absorb excess fluid. This increased pressure is called intracranial pressure (ICP) and requires draining of fluid to decrease the ICP. In some instances drugs such as mannitol or barbiturates can be used to decrease ICP. The cognitive and communication problems associated with brain injury are best treated as soon after the injury as possible. This early therapy will frequently center on increasing skills of alertness and attention, improving orientation to person, place, time, and situation, and stimulating speech understanding. Longer term rehabilitation may be performed depending upon the needs of the individual.
To date, no treatment option exists that is able to ameliorate cellular damage following brain injury, provide neuroprotection or induce the growth and development of new brain cells to replace damaged brain cells, any or all of which could help return the injured patient to normal or near normal function. Therefore, it is an object of the instant invention to provide such treatment options for brain injury patients.
Nervous System Disease—There are many different types of diseases of the nervous system. Some of these affect the central nervous system (i.e. ALS, Huntington's Disease, Parkinson's Disease), while others affect the peripheral nervous system (i.e. peripheral neuropathies). In most cases, regardless of the cause, the result of the disease is generally neurodegeneration and neuron death with associated loss of functional. Many treatments have been investigated, such as neurotrophic factors, most with limited success. In addition, various types of stem cells and cells having stem-like qualities are being investigated for their potential to treat and perhaps cure many diseases and disorders of the nervous system.
Over the past several decades, the concept of neural tissue grafting or exogenous stem cell transplantation has been investigated for its potential to treat central nervous system disorders. Current stem cell approaches have resulted in some limited therapeutic success but the establishment of long-term functional replacement is variable. It generally appears that the transplanted cells do not form or maintain the functional contacts essential for neuronal cell survival.
Much research has focused on driving the differentiation of stem cells in vitro using various growth factors and differentiation factors prior to implanting the cells. Other research has focused on driving the differentiation of stem cells in vivo, after implantation. Unfortunately, these methods have generated very little in the way of therapeutic successes to date.
Research suggests that several growth and differentiation factors may be involved in the proliferation, differentiation, migration and integration of stem cells into neural cells or tissues and that the particular factor, or combination of factors, may vary based on the type of neural cell desired (i.e. neuron, glial cell, etc.).
Examples of factors that encourage proliferation/expansion include IL-3, SCF, Flt-3 ligand, PDGF, EGF and FGF-2. A combination of several may be applied. For example, neuronal precursor cells have been expanded in the presence of both EGF and FGF-2. A specific example is provided by Lazzari, L., et al. (2001, Br J Haematol. 112(2):397-404) wherein, the highest expansion of cord blood hematopoietic stem cells was obtained with a combination containing Flt-3 ligand, thrombopoietin, IL-6 and IL-1.
Transcription factors such as Pax6 and Emx2 may be required for proliferation and patterning during neuronal development. Sonic hedgehog (SHH) is well known for its control of numerous processes during development as well as acting as a mitogen for embryonic neural stem cells. SHH may induce proliferation of adult stem cells. In the adult CNS, the actions of BMP and noggin are believed to regulate the balance between neurons and astrocytes.
TGF-β family members have been shown to have differentiation effects on ES cells (Schuldiner M., et al, PNAS USA. 2000 97(21):11307-12.) and neural crest stem cell differentiation (Shah N. M. Cell. 1996, 85(3):331-43; White P. M. Neuron. 2001, 29(1):57-71). Other agents that contribute to differentiation are Wnt factors, integrins, and extracellular matrix components. A mix of factors may be applied to differentiate a group of stem cells into a particular type of neuron. For example, FGF-2, ascorbic acid, SHH and FGF-8 have been used to differentiate mouse ES cells into dopaminergic and serotonergic neurons (Lee S. M. Nat Biotechnol. 2000, 18(6):675-9).
Unfortunately, to date, no treatment option exists that is able to ameliorate cellular damage associated with CNS disorders, provide neuroprotection to minimize additional cell damage or death, or induce the growth and development of new CNS cells to replace damaged, diseased or non-functional CNS cells, any or all of which could help return the patient to normal or near normal function. Therefore, it is an object of the instant invention to provide such treatment options for patients suffering CNS disorders.